Fig. 6: Proposed receptor activation models: dmIR, IR, and IGF1R.

a Insulin-induced IR activation at various insulin concentrations. Under unsaturated insulin conditions, IR adopts an Γ-shaped asymmetric conformation with one insulin bound or Ƭ-shaped asymmetric conformation with two insulins bound, both of which may exhibit partial receptor activity. Under saturated insulin conditions, IR adopts a T-shaped symmetric conformation with four insulins molecules bound, resulting in full receptor activity. b IGF-1 induced IGF1R activation. The Γ-shaped asymmetric conformation of IGF1R with only one IGF-1 bound has the full receptor activity, whereas the T-shaped symmetric conformation of IGF1R-P674G4 with two IGF-1 molecules bound shows lower receptor activity. c DmIR activation induced by DILP1, DILP2, or DILP5. DILP2 and DILP5 induce only asymmetric conformations of dmIR. DILP5 binding at site-2 stabilizes the asymmetric dmIR conformation and enhances receptor activation. DILP2, which lacks site-2 interaction and has a shorter A-chain N-terminus, forms a less stable asymmetric conformation and activates dmIR less potently than DILP5. In contrast, DILP1 induces both asymmetric and symmetric conformations of dmIR. The symmetric dmIR conformation shows lower receptor activity relative to the asymmetric form, likely due to the increased distance between the two membrane-proximal regions.